Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Chen, Xu-Qiao; Xing, Zhuo; Chen, Quang-Di; Salvi, Richard; Zhang, Xuming; Tycko, Benjamin; Mobley, William C.; Yu, Yichao

doi:10.3389/fnagi.2021.700280

Cited by 16 publications

(13 citation statements)

References 153 publications

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“…As one of the critical risk factors for early-onset Alzheimer’s disease (AD), trisomy 21 not only increases amyloid precursor protein ( APP ) gene dosage but also promotes the amyloidogenic pathway in the AD human brain by altering APP processing ( 1 – 3 ) and amyloid plaque deposition in the AD mouse brain ( 4 ). In addition to APP and BACE2, it remains to be determined whether other genes on chromosome 21 also contribute to AD pathology in DS ( 5 ) and the underlying molecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation

Zheng¹,

Song²,

Li³

et al. 2022

Journal of Clinical Investigation

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Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer’s disease (AD), implicating key roles for chromosome 21–encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene–mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and A β generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

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Section: Introductionmentioning

confidence: 99%

USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation

Zheng¹,

Song²,

Li³

et al. 2022

Journal of Clinical Investigation

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“…There are multiple factors that may contribute to the severity of the disease in Down syndrome. These include anatomical defects in the respiratory tract (e.g., airway malacia, smaller trachea) that cause obstructive sleep apnea [ 43 , 44 ], congenital heart defects that result in cardiopulmonary dysfunction and pulmonary hypertension [ 45 , 46 ], dysregulation of innate and adaptive immunity that leads to inflammatory and autoimmune responses [ 4 ], and premature aging that may lead to Alzheimer disease and immunosenescence [ 2 , 47 ]. Consistent with this interpretation, our data show that Dp16;ACE2 mice exhibited more severe clinical symptoms and lung histopathology than ACE2 mice following SARS-CoV-2 infection ( Figure 1 and Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Infection Causes Heightened Disease Severity and Mortality in a Mouse Model of Down Syndrome

Pechous,

Malaviarachchi,

Xing

et al. 2024

Biomedicines

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Recent epidemiological studies suggest that individuals with Down syndrome are more susceptible to SARS-CoV-2 infection and have higher rates of hospitalization and mortality than the general population. However, the main drivers behind these disparate health outcomes remain unknown. Herein, we performed experimental infections with SARS-CoV-2 in a well-established mouse model of Down syndrome. We observed similar SARS-CoV-2 replication kinetics and dissemination in the primary and secondary organs between mice with and without Down syndrome, suggesting that both groups have similar susceptibilities to SARS-CoV-2 infection. However, Down syndrome mice exhibited more severe disease as defined by clinical features including symptoms, weight loss, pulmonary function, and survival of mice. We found that increased disease severity in Down syndrome mice could not be attributed solely to increased infectivity or a more dramatic pro-inflammatory response to infection. Rather, results from RNA sequencing suggested that differences in the expression of genes from other physiological pathways, such as deficient oxidative phosphorylation, cardiopulmonary dysfunction, and deficient mucociliary clearance in the lungs may also contribute to heightened disease severity and mortality in Down syndrome mice following SARS-CoV-2 infection.

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“…In addition, advanced maternal age at conception (over 35 years) is associated with a type of congenital malformation [9] There is phenotype variability for all chromosomal abnormalities [13]. Several authors have emphasized that the phenotypic variability of Down's syndrome concerns many clinical signs of the disease, namely the importance of intellectual retardation, the inconstant presence of cardiopathy, or of a single transverse palmar crease, very early in the course of the development [15].…”

Section: Discussionmentioning

confidence: 99%

Correlation between Reasons for Prescription and Karyotype Results in Patients Referred for Suspected Chromosomal Abnormalities

Deh,

Dieth,

Coulibaly

et al. 2023

OJGen

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Karyotype prescription is based on clinical signs (or reasons for karyotype prescription) which are phenotypic manifestations associated with chromosomal abnormalities. The aim of this study was to establish a correspondence between karyotype indications and their results in patients. This was a retrospective study that was carried out in the Histology-Embryology-Cytogenetics laboratory of the University Hospital of Cocody-Abidjan from 2014 to 2019. 58 patient files were identified and included the indication or reason for prescribing a constitutional karyotype and the biological result obtained. An individual data sheet was used to collect the data. 17 reasons for prescription were identified and divided into 2 groups. Sexual ambiguity was the most frequent reason (29.3%). The first group (G1) represented the 10 reasons for which the karyotype results were normal. The second group (G2) corresponded of the 7 motives with normal or abnormal karyotype results. Several anomalies were listed according to these reasons: inversions, mosaics (anomalies of number and structure) and trisomy 21. The last was the most frequent chromosomal anomaly (69.24%). It was found in several reasons for karyotype prescription: malformations, neurological disorders, suspected trisomy and cardiac pathology. Several factors could explain these results, among which are the limits of the karyotype and the non-genetic causes that can induce these abnormal phenotypes. Complementary examinations to the karyotype are molecular cytogenetic techniques, notably fluorescence in situ hybri-

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Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Cited by 16 publications

References 153 publications

USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation

USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation

SARS-CoV-2 Infection Causes Heightened Disease Severity and Mortality in a Mouse Model of Down Syndrome

Correlation between Reasons for Prescription and Karyotype Results in Patients Referred for Suspected Chromosomal Abnormalities

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